Ciploxx 250mg / 500mg Tablets

CIPLOXX is indicated for the treatment of severe and/or complicated infections caused by ciprofloxacin sensitive bacteria where other antimicrobials, approved for a similar indication and to which the causative bacteria are sensitive, were considered not to be an appropriate treatment option, have failed, are contraindicated or not tolerated. CIPLOXX is not indicated / approved for the initiation of treatment (first line treatment) of infections described as mild / moderate / acute and uncomplicated, caused by bacteria sensitive to ciprofloxacin, unless treatment with other appropriate antimicrobials, approved for a similar indication and to which the causative bacteria are sensitive, have failed, are contraindicated or not tolerated. CIPLOXX is indicated for the treatment of the following infections, where these infections are compliant with the indication context:

• Severe and/or complicated lower respiratory tract infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae.
• Severe and/or complicated urinary tract infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus epidermidis, Streptococcus faecalis.
• Skin and soft tissue infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes.
• Severe and/or complicated gastrointestinal infections Infective diarrhoea caused by Escherichia coli, Campylobacter jejuni, Shigella flexneri and Shigella sonnei.
• Severe and/or complicated bone infections Osteomyelitis due to susceptible Gram-negative organisms.
• Gonorrhoea CIPLOXX is ineffective against Treponema pallidum (see section 5.1. u02baInherently resistant organismsu02ba).

In the treatment of infections caused by Pseudomonas aeruginosa, an aminoglycoside must be administered concomitantly. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to CIPLOXX. Therapy with CIPLOXX may be initiated in severe and/or complicated infections before results of these tests are known; once results become available, appropriate therapy should be continued.

Posology The dosage range is 250 to 750 mg twice daily. The duration of treatment to contain and eradicate infection depends upon the type and severity of the infection, immunological status, clinical response and bacteriological findings. Use the lowest effective dose for the shortest time to contain and eradicate the infection.

Infections of the lower respiratory tract Severe and/or complicated: 750 mg twice daily. In cystic fibrosis patients: 750 mg twice daily. The low body mass of these patients should, however, be taken into consideration when determining the dosage (7,5 to 15 mg/kg/day). Infections of the urinary tract Severe and/or complicated: 500 mg twice daily. Infections of the skin Severe and/or complicated: 750 mg twice daily. Infectious diarrhoea 500 mg twice daily. Bone infections Severe and/or complicated: 750 mg twice daily. Treatment may be required for 4 to 6 weeks or longer. Gonorrhoea: A single dose of 250 mg.

Special populations Elderly Elderly patients should be treated with the lowest possible dose; this will depend on the creatinine clearance and on the severity of the illness. If the patient is unable to take oral ciprofloxacin, as in CIPLOXX, due to the severity of the illness or for other reasons (e.g. patients on enteral nutrition), it is recommended to start treatment with intravenous ciprofloxacin. Following intravenous administration, the treatment may be continued orally.

Impaired renal or liver function In patients with reduced renal function, the half-life of CIPLOXX may be prolonged. The dosage needs to be adjusted as shown below. For patients with changing renal function, or patients with renal impairment and hepatic insufficiency, monitoring of medicine serum levels provides the most reliable basis for dose adjustment. Dose adjustment of ciprofloxacin, as in CIPLOXX, for patients with renal and/or hepatic impairment:

• Renal insufficiency: Creatinine clearance (CLcr) (mL/min/1,73 m2) Dose 1.1 31 u2264 CL cr u2264 60 Maximum 1000 mg/day orally 1.2 CLcr u2264 30 Maximum 500 mg/day orally 1.3 Impaired renal function and haemodialysis As in 1.2 above; on dialysis days after dialysis.
• Renal impairment and CAPD (chronic ambulatory peritoneal dialysis): 2.1 Oral administration of CIPLOXX tablets as 1 x 500 mg tablet or 2 x 250 mg tablets are indicated. 2.2 For CAPD patients with peritonitis, the recommended daily oral dose is 500 mg four times a day.
• Hepatic impairment: No dose adjustment.
• Hepatic and renal impairment: As in 1.1 and 1.2 above.

Method of administration CIPLOXX tablets should be swallowed whole with plenty of liquid and may be taken with or without meals. If CIPLOXX is taken on an empty stomach, the active substance is absorbed more rapidly. If taken with dairy products or with mineral fortified drinks, reduced absorption of CIPLOXX may be expected. CIPLOXX should not be taken concurrently with dairy products or with mineral fortified drinks alone (e.g. yoghurt, milk, calcium fortified orange juice). Dietary calcium as part of a meal, however, does not significantly affect absorption.

CIPLOXX is contraindicated in children under the age of 18 years and in growing adolescents. Experimental evidence indicates that species variable reversible lesions of the cartilage of weight-bearing joints have occurred in immature members of certain animal species. CIPLOXX is contraindicated in:

• Patients with known a history of hypersensitivity to ciprofloxacin, any other quinolones, or to any of the inactive ingredients of excipients in CIPLOXX (see section 6.1). Updated in line with current SAHPRA PI Guideline.
• Pregnancy and lactation (see section 4.6).
• Patients receiving tizanidine concomitantly (see section 4.5).
• Concomitant use of fluoroquinolones with ACE inhibitors / angiotensin receptor blockers in patients with moderate to severe renal impairment and in the elderly.
• Concomitant use of ciprofloxacin with other medicines known to prolong the QT interval, or in patients with disorders that prolong the QT interval to such an extent that it leads to prolonged QTcF interval known to be associated with serious and potentially fatal dysrhythmias, or if symptomatic dysrhythmias occur with concomitant use at time intervals shorter than QT intervals usually associated with dysrhythmias.
• A history of tendon, muscle, joint, nerve, central nervous system, epilepsy or psychotic disorders especially those related to previous quinolone / fluoroquinolone use where alternative, appropriate antibiotic choices are available for treatment.
• Myasthenia gravis where alternative appropriate antibiotic choices are available to treat these patients.
• Aortic aneurysm and/or dissection or in patients with risk factors or conditions predisposing for aortic aneurysm and/or dissection if alternative appropriate antibiotic choices are available.
• Patients with confirmed mitral valve and/or aortic valve regurgitation unless no safer appropriate alternative antibiotic is available, has failed or is not well tolerated.

Streptococcal infections (including Streptococcus pneumoniae) CIPLOXX is not recommended for the treatment of streptococcal infections due to inadequate efficacy. Severe cutaneous adverse reactions Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN) Stevens Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with CIPLOXX (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions and be closely monitored. If signs and symptoms suggestive of these reactions appear, CIPLOXX should be discontinued immediately, and an alternative treatment should be considered. If the patient has developed a serious reaction such as SJS, TEN or DRESS with the use of CIPLOXX, treatment with CIPLOXX must not be restarted in this patient at any time.

Severe infections and/or infections due to Gram-positive or anaerobic bacteria Monotherapy with CIPLOXX is not suited for treatment of severe infections and infections that may be due to Gram-positive or anaerobic pathogens. CIPLOXX must be co-administered with other appropriate antibacterial medicines in such infections. CIPLOXX should not be used in staphylococcal infections and infections involving anaerobic bacteria.

Genital tract infections Gonococcal urethritis, epididymo-orchitis, cervicitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant isolates of Neisseria gonorrhoeae. Therefore, CIPLOXX should only be used for the treatment of gonococcal urethritis or cervicitis if ciprofloxacin-resistant Neisseria gonorrhoeae can be excluded. For epididymo-orchitis and pelvic inflammatory diseases, empirical ciprofloxacin, as in CIPLOXX, should only be considered in combination with another suitable antibacterial medicine (such as a cephalosporin), unless ciprofloxacin-resistant Neisseria gonorrhoeae can be excluded. The treatment should be reconsidered if clinical improvement is not achieved after 3 days of treatment.

Urinary tract infections Resistance of Escherichia coli (the most common pathogen involved in urinary tract infections) to fluoroquinolones, including CIPLOXX, varies. Prescribers are advised to take the local prevalence of resistance into consideration.

Intra-abdominal infections There is limited data available on the efficacy of CIPLOXX in the treatment of post-surgical intra-abdominal infections.

Travellers' diarrhoea The resistance of relevant pathogens to ciprofloxacin, as in CIPLOXX, in the countries visited should be taken into consideration.

Infections of the bones and joints Depending on microbiological results, CIPLOXX should be used in combination with other antimicrobial medicines.

Complicated urinary tract infections and pyelonephritis Treatment of urinary tract infections with CIPLOXX should be considered when other treatments cannot be used and should be based on microbiological results.

Other specific severe infections CIPLOXX may be used in other severe infections, when other treatments cannot be used, or after failure of conventional therapy and when the microbiological results can justify the use of CIPLOXX, in accordance with official guidance, or after careful benefit-risk evaluation. The use of CIPLOXX for specific severe infections other than those mentioned above has not been evaluated and clinical experience is limited.

Hypersensitivity Anaphylactic / anaphylactoid reactions can occur (e.g. facial, vascular and laryngeal oedema, dyspnoea progressing to life-threatening shock), in some instances after the first administration. In these cases, CIPLOXX should be discontinued and appropriate medical treatment instituted (see section 4.8).

Prolonged, disabling and potentially irreversible serious adverse drug reactions Cases of prolonged (continuing for months or years), disabling and potentially irreversible serious adverse medicines reactions affecting different, sometimes multiple, body systems (including musculoskeletal, nervous, psychiatric and senses) have been reported in patients receiving quinolones and fluoroquinolones such as CIPLOXX irrespective of their age and pre-existing risk factors. CIPLOXX should be discontinued immediately at the first signs or symptoms of any serious adverse reaction and patients should be advised to contact their prescriber for advice.

Children and adolescents CIPLOXX is contraindicated in children less than 18 years. In children arthropathy is reported to occur commonly (see additional information on special populations).

Musculoskeletal system CIPLOXX may exacerbate the symptoms of myasthenia gravis. The use of CIPLOXX in patients with myasthenia gravis is contraindicated if alternative appropriate antibiotic choices are available (see section 4.3). CIPLOXX should not be used in patients with a history of tendon disorders, especially those related to previous exposure to quinolone or fluoroquinolone use (see section 4.3). However, in very rare instances, after microbiological testing and evaluation of the risk / benefit balance, CIPLOXX may be used in these patients for the treatment of certain severe infections, particularly in the event of standard treatment failure or bacterial resistance.

Tendinitis and tendon rupture Tendinitis and tendon rupture (especially but not limited to the Achilles tendon), sometimes bilateral, may occur with CIPLOXX, even within the first 48 hours of treatment. Tendon inflammation and ruptures may occur up to several months after CIPLOXX discontinuation. The risk of tendinopathy may be increased in elderly patients, during strenuous physical activity, in patients with renal impairment, patients with solid organ transplants or in patients concomitantly treated with corticosteroids (see section 4.5). Therefore, concomitant use of corticosteroids should be avoided. CIPLOXX should be discontinued at any sign of tendinitis (e.g. painful swelling, inflammation). Care should be taken to keep the affected limb at rest. Physical exercise should be avoided, and a medical practitioner consulted.

Photosensitivity CIPLOXX has been shown to cause photosensitivity reactions. Patients should be advised to avoid direct exposure to excessive sunlight or UV-light while taking CIPLOXX. If photosensitisation (i.e. sunburn-like skin reactions) occurs, treatment should be discontinued (see section 4.8).

Central nervous system CIPLOXX should be used with caution in patients with a history of convulsive disorders. CIPLOXX is known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. In epileptic patients and patients who have suffered from previous CNS disorders (e.g. previous history of convulsion, lowered convulsion threshold, reduced cerebral blood flow, stroke or altered brain structure), CIPLOXX should only be used where alternative appropriate therapies have failed, are contraindicated or not tolerated, since these patients are endangered due to possible central nervous system side effects. Cases of status epilepticus have been reported (see section 4.3 and section 4.8). CIPLOXX should only be used where the benefits exceed the risks, as these patients have an increased risk of possible central nervous system side effects. If seizures occur, CIPLOXX should be discontinued (see section 4.8). In some instances, CNS reactions occurred after the first administration of CIPLOXX. Depression or psychosis can rarely progress to suicidal ideation / thoughts culminating in attempted suicide or completed suicide. In these cases, CIPLOXX must be discontinued and the medical practitioner informed immediately. In patients receiving CIPLOXX, cases of polyneuropathy (based on neurological symptoms including pain, burning, muscle weakness or sensory disturbances, alone or in combination) have been reported. In order to prevent the development of an irreversible condition, CIPLOXX should be discontinued in patients experiencing symptoms of neuropathy, such as pain, tingling, burning, numbness, and/or weakness (see section 4.8).

Cardiac disorders There is some evidence of an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the elderly population. Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet's disease, hypertension, known atherosclerosis). In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a medical practitioner in an emergency department of a hospital. CIPLOXX has been associated with QT prolongation (see sections 4.2 and 4.8). Concomitant use of CIPLOXX with medicines or in patients with disorders that can result in prolongation of the QT interval is contraindicated if concomitant use leads to prolongation of QTc interval associated with serious or potentially fatal dysrhythmias, or symptomatic dysrhythmias occur at QTc intervals less than usually associated with dysrhythmias (e.g. class lA or Ill antidysrhythmics, tricyclic antidepressants, macrolides, antipsychotics), (see section 4.5) or congenital long QT syndrome, risk of Torsades de Pointes, uncorrected electrolyte imbalance such as hypokalaemia or hypomagnesaemia, and cardiac disease such as heart failure, myocardial infarction, or bradycardia.

A pre-treatment ECG and frequent follow up ECG monitoring is mandatory with concomitant use to determine whether concomitant use is contraindicated. There is some evidence of an increased risk of aortic aneurysm and/or dissection after intake of fluoroquinolones, particularly in the elderly population. Fluoroquinolones, such as CIPLOXX, should only be used in patients at risk if no other treatment options are available (see section 4.3). Patients at risk are patients with a positive family history of aneurysmal disease, pre-existing aortic disease and/or dissection or other risk factors or conditions predisposing to aortic aneurysm and dissection e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet's disease, hypertension and known atherosclerosis. In case of sudden abdominal, chest or back pain, patients should be advised to immediately go to their medical practitioner or a hospital emergency department. There is some evidence, although inconclusive, of a possible association between oral fluoroquinolone use, such as CIPLOXX, and mitral valve and/or aortic valve regurgitation. A thorough cardiovascular examination including an echocardiogram, should be performed before oral fluoroquinolones are prescribed. Fluoroquinolones, including CIPLOXX, should not be prescribed to patients with mitral valve and/or aortic valve regurgitation (see section 4.3). Concomitant use of fluoroquinolones and ACE inhibitors / angiotensin receptor blockers may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3). Renal function should be assessed before initiation of treatment and monitored during treatment with fluoroquinolones and ACE inhibitors / angiotensin receptor blockers. Women and the elderly may be more sensitive to QTc-prolonging medicines. Therefore, caution should be taken when fluoroquinolones, including CIPLOXX, are administered in these populations (see section 4.2 and section 4.8).

Disturbances in blood glucose Disturbances in blood glucose, including both hyperglycaemia and hypoglycaemia have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic medicine or with insulin, and in the elderly. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended (see section 4.5. and section 4.8).

Gastrointestinal system The development of severe and persistent diarrhoea during or after treatment (including several weeks after treatment), may indicate pseudomembranous colitis, which may be life-threatening with possible fatal outcome, and requires immediate treatment (see section 4.8). In such cases, CIPLOXX must be discontinued immediately and appropriate therapy initiated (e.g. vancomycin, orally 4 x 250 mg/day). In this situation, anti-peristaltic medicines are contraindicated.

Renal and urinary system Crystalluria has occurred with the use of CIPLOXX. Patients receiving CIPLOXX should be well hydrated and excessive alkalinity of the urine should be avoided.

Impaired renal function In patients with impaired renal function, dosage adjustment is needed to avoid an increase in adverse reactions due to accumulation of CIPLOXX, since ciprofloxacin is largely excreted unchanged via renal pathway (see section 4.2). Concomitant use of fluoroquinolones, such as CIPLOXX, and ACE inhibitors / angiotensin receptor blockers may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3). Renal function should be assessed before initiating treatment, and monitored during treatment, with CIPLOXX and ACE inhibitors / angiotensin receptor blockers.

Hepatobiliary system Hepatic necrosis and life-threatening hepatic failure have been reported with CIPLOXX (see section 4.8). Treatment should be discontinued if any signs or symptoms of hepatic disease develop, such as jaundice, anorexia, dark urine, tender abdomen or pruritus. There can be a temporary increase in transaminases, alkaline phosphatase or cholestatic jaundice, especially in patients with previous liver damage.

Glucose-6-phosphate dehydrogenase deficiency In patients with glucose-6-phosphate dehydrogenase deficiency, haemolytic reactions have been reported with CIPLOXX. Unless the benefit is considered to outweigh the risk, CIPLOXX should be avoided in these patients. The potential occurrence of haemolysis should be monitored.

Resistance Long-term or repeated administration of CIPLOXX can lead to superinfections with resistant bacteria or fungi. During or following a course of treatment with CIPLOXX, bacteria that demonstrate resistance to ciprofloxacin may be isolated, with or without a clinically apparent superinfection. There may be a particular risk of selecting for ciprofloxacin-resistant bacteria during extended durations of treatment and when treating nosocomial infections and/or infections caused by Staphylococcus and Pseudomonas species.

Cytochrome P450 CIPLOXX inhibits CYP1A2 and may therefore cause increased serum concentrations of concomitantly administered medicines metabolised by this enzyme (e.g. tizanidine, theophylline, olanzapine, clozapine, ropinirole, duloxetine, agomelatine). Co-administration of CIPLOXX and tizanidine is contraindicated (see section 4.3). Therefore, patients taking these medicines concurrently with CIPLOXX should be monitored closely for signs of overdose, and determination of serum concentrations (e.g. of theophylline) may be required (see section 4.5).

Effects of other medicines on CIPLOXX Medicines known to prolong QT interval CIPLOXX should be used with care in patients receiving medicines known to prolong QT interval (e.g. Class IA and III antidysrhythmics, macrolides, tricyclic antidepressants, antipsychotics) (see section 4.3). Chelation complex formation CIPLOXX tablets should be administered 1 to 2 hours before, or at least 4 hours after taking multivalent cation-containing medicines and mineral supplements, (e.g. magnesium, calcium, aluminium or iron preparations), antacids or sucralfate, polymeric phosphate binders (e.g. sevelamer or lanthanum carbonate), and highly buffered medicines (e.g. didanosine or other antiretrovirals) containing aluminium, magnesium or calcium, as interference with absorption may occur. This restriction does not apply to antacids belonging to the class of H2-receptor blockers. Food and dairy products The concurrent administration of dairy products or mineral fortified drinks alone (e.g. yoghurt, milk, calcium fortified orange juice) with CIPLOXX should be avoided because the absorption of CIPLOXX is reduced. Dietary calcium as part of a meal, however, does not significantly affect absorption. Non-steroidal anti-inflammatory medicines (NSAIDs) Concomitant administration of the non-steroidal anti-inflammatory medicine fenbufen with quinolones may increase the risk of central nervous system stimulation and seizures.

Probenecid Probenecid interferes with renal secretion of CIPLOXX. Co-administration of probenecid and CIPLOXX increases the CIPLOXX serum concentrations. Metoclopramide Metoclopramide accelerates the absorption of CIPLOXX, resulting in a shorter time to reach maximum plasma concentrations. No effect on the bioavailability of CIPLOXX was observed. Omeprazole Co-administration of CIPLOXX and omeprazole results in a 20 % reduction of the Cmax and AUC of CIPLOXX.

Effects of CIPLOXX on other medicines Tizanidine Tizanidine must not be co-administered with CIPLOXX (see section 4.3), as it increases serum tizanidine concentrations (7-fold increase in Cmax, 10-fold increase in AUC, on average). Increased serum tizanidine concentrations are associated with potentiation of hypotensive and sedative effects. Agomelatine Fluvoxamine, a strong inhibitor of CYP450 1A2, markedly inhibits the metabolism of agomelatine resulting in a 60-fold increase of agomelatine exposure. Although no data are available for CIPLOXX, a moderate inhibitor of CYP450 1A2, similar effects may be expected (see section 4.4). Zolpidem Co-administration of CIPLOXX may increase blood levels of zolpidem, concurrent use is not recommended.

Methotrexate Renal tubular transport of methotrexate may be inhibited by co-administration of CIPLOXX, potentially resulting in increased methotrexate plasma levels and an increased risk of methotrexate associated toxic reactions. Therefore, patients receiving treatment with methotrexate should be carefully monitored when concomitant treatment with CIPLOXX is indicated. Concomitant use is, however, not recommended (see section 4.4).

Theophylline Concurrent administration of CIPLOXX with theophylline may lead to elevated plasma concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related toxicity and may rarely be life-threatening or fatal. If concomitant use cannot be avoided, plasma levels of theophylline should be monitored, and dosage adjustments made as appropriate (see section 4.4).

Other xanthine derivatives Co-administration of CIPLOXX and caffeine or pentoxifylline (oxpentifylline), caused raised serum concentrations of these xanthine derivatives. Phenytoin Simultaneous administration of phenytoin and CIPLOXX may cause increased or reduced phenytoin serum levels, to such an extent that monitoring of medicine levels is recommended. Ciclosporin Frequent monitoring of serum creatinine concentrations (twice a week) is advised in patients on concomitant ciclosporin therapy, as transient increases in serum creatinine concentrations have been observed.

Vitamin K antagonists The simultaneous administration of CIPLOXX and warfarin (a vitamin K antagonist) may augment its anticoagulant effects. The risk may vary with the underlying infection, general status and age of the patient so that it is difficult to assess the contribution of CIPLOXX to the increase in INR (international normalised ratio). Therefore, the INR should be closely monitored during and shortly after co-administration.

Glibenclamide Concurrent administration of CIPLOXX and glibenclamide can potentiate the action of glibenclamide, leading to hypoglycaemia (see section 4.4).

Duloxetine Concurrent use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme, such as fluvoxamine, may result in an increase of AUC and Cmax of duloxetine. Although no data are available on a possible interaction with CIPLOXX, similar effects may be expected with co-administration (see section 4.4).

Ropinirole Concurrent use of ropinirole with CIPLOXX, a moderate inhibitor of the CYP450 1A2 isozyme, results in an increase in ropinirole Cmax of 60 % and AUC of 84 %. During and shortly after co-administration with CIPLOXX, monitoring of ropinirole-related side effects and dose adjustment, if required, are recommended (see section 4.4).

Lidocaine (lignocaine) Concurrent use of lidocaine (lignocaine) containing medicines with CIPLOXX, a moderate inhibitor of CYP450 1A2 isozyme, reduces clearance of intravenous lidocaine by 22 %. Although lidocaine treatment was well tolerated, a possible interaction with CIPLOXX, associated with side effects may occur upon co-administration.

Clozapine After co-administration of 250 mg ciprofloxacin, as in CIPLOXX, with clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29 % and 31 %, respectively. During and shortly after co-administration with CIPLOXX, clinical surveillance and appropriate adjustment of clozapine dosage are advised (see section 4.4).

Sildenafil Following an oral dose of 50 mg sildenafil given concurrently with 500 mg ciprofloxacin, as in CIPLOXX, in healthy subjects, sildenafil Cmax and AUC were increased about two-fold. Therefore, care should be taken when prescribing CIPLOXX with sildenafil, taking into consideration the risks and the benefits.

ACE inhibitors / renin-angiotensin receptor blockers Concomitant use of fluoroquinolones, such as CIPLOXX, and ACE inhibitors / angiotensin receptor blockers may precipitate acute kidney injury (see section 4.3). Careful consideration should be given to age, renal function, hydration status and concomitant prescribing of diuretics or NSAIDs, and to monitoring of changes in renal function throughout treatment.

Pregnancy Safety in pregnancy has not been established (see section 4.3).

Breastfeeding CIPLOXX is excreted in breast milk. Due to the potential risk of articular damage, CIPLOXX should not be used during lactation.

Due to its neurological effects, CIPLOXX may affect reaction time. The ability to drive a motor vehicle or operate machinery may be impaired by CIPLOXX, even when taken as prescribed. This applies particularly in combination with alcohol.

Infections and infestations Frequent Moniliasis. Less frequent: Mycotic superinfections, pseudomembranous colitis, antibiotic associated colitis (with possible fatal outcome).

Blood and lymphatic system disorders Frequent: Eosinophilia, leukopenia. Less frequent Granulocytopenia, anaemia, thrombocytopenia, leucocytosis, thrombocythemia (thrombocytosis) haemolytic anaemia, altered prothrombin values, pancytopenia (life-threatening), bone marrow suppression (life-threatening), neutropenia, agranulocytosis.

Immune system disorders Less frequent: Allergic reaction, medicine fever, anaphylactoid (anaphylactic) reaction, anaphylactic shock (life-threatening), pruritic rash, allergic oedema / angioedema, serum sickness- like reaction.

Endocrine disorders Frequency unknown: Syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

Metabolism and nutrition disorders Less frequent: Hyperglycaemia, hypoglycaemia, particularly in diabetic patients (see section 4.4 and section 4.5), decreased appetite and food intake. Frequency Unknown: Hypoglycaemic coma.

Psychiatric disorders Frequent: Insomnia, agitation, confusion. Less frequent: Anxiety reaction, abnormal dreams (nightmares), hallucinations, psychotic reactions (potentially culminating in suicidal ideation or suicide attempts and completed suicide) depression (potentially culminating in suicidal ideation or suicide attempts and completed suicide) psychomotor hyperactivity, disorientation, sleep disorders. Frequency Unknown: Mania, including hypomania.

Nervous system disorders Frequent: Dizziness, headache, taste perversion. Less frequent: Paraesthesiau2019s (peripheral paralgesia), unsteady gait, convulsions, grand mal convulsion, including status epilepticus, intracranial hypertension and pseudo tumour cerebri tremor (trembling), hypaesthesia, taste loss (impaired taste) dysaesthesia, migraine, disturbed coordination, olfactory nerve disorders. Frequency unknown: Peripheral neuropathy, polyneuropathy.

Eye disorders Less frequent Abnormal vision (visual disturbances), e.g. diplopia, chromatopsia.

Ear and labyrinth disorders Less frequent: Tinnitus, transient deafness / impairment of hearing (especially at high frequencies), hearing loss, vertigo.

Cardiac disorders Less frequent: Tachycardia. Frequency unknown: Ventricular dysrhythmia, torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), prolonged ECG QT.

Vascular disorders Frequent: Thrombo-phlebitis. Less frequent: Vasodilation (flushing) syncope, hypotension, oedema peripheral, vascular, face, vasculitis.

Respiratory, thoracic and mediastinal disorders Less frequent: Dyspnoea (including asthmatic condition), larynx oedema.

Gastrointestinal disorders Frequent: Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain, anorexia, flatulence. Less frequent: Moniliasis (oral and gastrointestinal), gastrointestinal pains, pancreatitis, decreased appetite.

Hepatobiliary disorders Frequent: Increased alkaline phosphatase, abnormal liver function tests, bilirubinaemia. Less frequent: Cholestatic jaundice, jaundice, hepatitis, increased transaminases, hepatic impairment, cholestatic icterus, hepatic necrosis (very seldom progressing to life-threatening hepatic failure).

Skin and subcutaneous tissue disorders Frequent: Rashes, urticaria, pruritus, maculopapular rash. Less frequent: Photosensitivity reaction, erythema nodosum, erythema multiforme (minor), Stevens-Johnson syndrome (potentially life-threatening), petechiae, haemorrhagic bullae, papules, crust formation with signs of vasculitis, toxic epidermal necrolysis (potentially life-threatening). Frequency unknown: Acute generalised exanthematous pustulosis (AGEP), DRESS (medicine reaction with eosinophilia and systemic symptoms syndrome).

Musculoskeletal, connective tissue and bone disorders Frequent: Joint pain (arthralgia). Less frequent: Joint disorder (joint swelling), muscular weakness, myalgia / muscular pain, tendinitis, tendon rupture (predominantly Achilles tendon), musculoskeletal pain (e.g. extremity pain, back pain, chest pain), arthritis, increased muscle tone and cramping, exacerbation of symptoms of myasthenia gravis.

Renal and urinary disorders Less frequent: Crystalluria, interstitial nephritis, tubulointerstitial nephritis, renal impairment, renal failure, haematuria, abnormal kidney function.

Reproductive system and breast disorders Less frequent: Vaginal moniliasis.

General disorders and administrative site conditions Frequent: Asthenia (general feeling of weakness, tiredness). Less frequent: Pain, fever, sweating (hyperhidrosis).

Investigations Frequent: Increased SGOT / AST, increased SGPT / ALT, increased creatinine, increased urea (BUN). Less frequent: Increased amylase, increased lipase. Frequency unknown: Increased INR (in patients treated with vitamin K antagonists).

Post-marketing Infections and infestations Less frequent: Life-threatening pseudomembranous colitis with possible fatal outcomes. Blood and lymphatic system disorders Less frequent: Petechia (punctate skin haemorrhages), pancytopenia, agranulocytosis, marrow depression.

Immune system disorders Less frequent: Serum sickness like reaction. Metabolism and nutrition disorders Frequency unknown: Hyperglycaemia, hypoglycaemic coma (see section 4.4 and section 4.5).

Psychiatric disorders Less frequent: Psychosis. Nervous system disorders Less frequent: Intracranial hypertension, ataxia, hyperesthesia, hypertonia, twitching, parosmia (impaired smell), anosmia (usually reversible on discontinuation).

Cardiac disorders Frequency unknown: Cases of mitral valve and/or aortic valve regurgitation were reported in patients treated with oral fluoroquinolones, such as CIPLOXX. Due to insufficient post-marketing information in the reported cases, it is unknown whether fluoroquinolone use was the causative factor, or a contributory factor or played no role in the reported cases where mitral and/or aortic regurgitation cases was diagnosed.

Gastrointestinal disorders Less frequent: Pancreatitis. Hepatobiliary disorders Less frequent: Liver necrosis (very seldom progressing to life-threatening hepatic failure). Skin and subcutaneous tissue disorders Less frequent: Stevens-Johnson syndrome, epidermal necrolysis (Lyellu2019s syndrome), fixed eruption.

Musculoskeletal, connective tissue and bone disorders Less frequent: Tendinitis (predominantly achillotendinitis), partial or complete tendon rupture (predominantly Achilles tendon), myasthenia, exacerbation of symptoms of myasthenia gravis.

Mild symptoms of toxicity have been reported with an overdose of 12 g. Acute renal failure has been reported with an acute overdose of 16 g. Symptoms of overdose are dizziness, headache, tremor, tiredness, hallucinations, seizures, confusion, renal and hepatic impairment, abdominal discomfort as well as crystalluria and haematuria. In the event of acute, excessive oral overdosage, reversible renal toxicity has been reported. Apart from routine emergency measures, e.g. ventricular emptying followed by medical carbon, it is recommended to monitor renal function (including urinary pH, and to acidify to prevent crystalluria, if required). Patients should be kept well hydrated. Calcium or magnesium containing antacids may theoretically reduce the absorption of CIPLOXX in overdoses. Only a small amount of ciprofloxacin, as in CIPLOXX, (< 10 %) is removed from the body after haemodialysis or peritoneal dialysis. Treatment is symptomatic and supportive. Due to the possibility of QT interval prolongation, ECG monitoring should be undertaken.